Marla Dubinsky, MD, on Therapeutic Drug Monitoring

In this video, Dr. Dubinsky reviews a panel discussion on therapeutic monitoring of anti-TNF levels in patients with inflammatory bowel disease, presented December 11 at AIBD 2020.

Marla Dubinsky, MD, is codirector of the Susan and Leonard Feinstein IBD Center at the Icahn School Medicine at Mount Sinai in New York.

TRANSCRIPT

Hello. I'm Dr. Marla Dubinsky from the Icahn School of Medicine, Mount Sinai, New York. I want to talk to you a little bit about our breakout session today, at Advances in Inflammatory Bowel Disease, that was focused on therapeutic drug monitoring.

It was really a nice case that was presented. Let me walk you through some of the highlights. It was a case of a 67-year-old male who had been on infliximab for at least 4 years and had been doing well, including deep mucosal healing with endoscopic remission and histologic remission.

There was a drug concentration and anti-drug antibody level drawn. It showed that the patient actually had low antidrug antibodies. It was 5.1. The drug concentration was 7.1, which is within the therapeutic range.

The question which started a long debate as to what to do now. Some would have said, "The patient's doing well. Why are you even checking a drug concentration?" Those of us who are proactive therapeutic drug monitoring, in that camp, would propose that maybe annually we would check a drug concentration because we do know patients, over time, can develop antidrug antibodies.

There are many different opinions. Myself, in that proactive camp, I actually said that I have seen patients who have both low drug concentration as well as low drug antibodies. Low is deemed less than 10. This is using the mobility shift assay at Prometheus.

My advice was to bring the patient in 1 or 2 weeks earlier. The patient was on 5 mg/kg every 8 weeks. I had suggested maybe to bring the patient in a little bit earlier. I wasn't proposing escalating the dose but just maybe trying to get the trough drug concentration a little higher to try and push down those antibodies.

Others on the call said just leave it as is. Others would have proposed maybe repeating. We had a little bit of a discussion around the fact that maybe you shouldn't even be doing it, as I noted.

Then, of course, the patient had a repeat drug concentration, because that was the suggestion, is that maybe just double-check and repeat. Unfortunately, the patient had a drug concentration but not using the same assay. His drug concentration didn't drop that much. He continued actually per, I believe it was the Mayo Clinic assay, which, again, only reports antibodies in the face of no detectable drug concentration, said that there was a lower level of drug concentration in the 2s.

Again, question was patient still remains well. This is a year after the original check. Patient started to lower their drug concentration. Antibody levels weren't budging. Then the patient, another year later, had another therapeutic drug monitoring assay. That was done at LabCorp. The patient, interestingly, actually had even lower drug concentration, but the antibodies remained negative.

At that point, actually, the patient was escalated in dose from 5 q8 to 7.5 mg every 8 weeks. Then the patient continued to do well and had a drug concentration which suggested that the patient's levels actually were lower.

The decision at that point was actually whether or not the patient, who continues to do well, should even stay on drug. Dose of 7.5 mg/kg continued. Patient then noted that they felt that their hair was falling out and they were having some skin issues. It was really bothering them. They wanted to stop.

At that point, the drug was actually stopped. The patient was transitioned to 5-ASAs, actually. Lo and behold, about 10 months after completely stopping the infliximab, the patient actually had a flare. He had a repeat endoscopy, which showed that the patient had endoscopic activity. That's where it all began to have a lot of different decisions.

Some had noted, Dr. [Brian] Feagan, for example, who was on the call as well, said, "You know what? The patient did really well with anti-TNF. I know he had a low-level antibody at the beginning. I think that you should resume anti-TNF and not with combination." There was also that discussion because maybe could we have added an immunomodulator.

Way back when he first presented with these low-level antibodies, could we have lowered that antibody level by actually adding immunomodulator. Dr. Feagan felt there's no animal data to support that, but there is some human data. There are reports that when you added methotrexate or thiopurine, you may have actually been able to reduce the antibody level and maybe increase the drug concentration.

The concept was he was 67. Is now really the time to be adding combination therapy? He did OK on monotherapy historically. Ashwin [Ananthakrishnan, MD], who was also on the call, said, "Maybe you should try another TNF. Does he really need to do infliximab? Is there an issue of antibody development when you've had a honeymoon?"

This brought in a lot of different aspects about therapeutic drug monitoring. Dr. Feagan had said that if he did not want to go back on infliximab because of the skin and the hair issues...Interestingly Dr. [Hans] Herfarth said that he didn't see the skin manifestation, so there was a discussion that maybe we could restart.

Brian said if the patient was hesitant to go back on for skin-related issues, he would go with vedolizumab. He may have considered doing actually combination therapy. Ashwin noted that he would try within the TNF but try a different TNF, such as adalimumab or golimumab.

Myself, I said actually I would go with vedolizumab. I did note that the patient is 67. He wouldn't need combination therapy. The data does not suggest, in any way, in any trial or even post-trial, that you need a combination therapy when you actually use ustekinumab or vedolizumab.

Granted, that wasn't agreed upon. There was discussion that it may be OK to start him on combination therapy. For me, he was 67. I said we should try vedolizumab.

Then the question came to, "All right, so you're all excitable about proactive therapeutic drug monitoring in the TNFs, particularly infliximab, which is where we have the most data. What would you do with drug levels when it came to vedolizumab and ustekinumab?"

I'm enthusiastic about proactive TDM. What I did say is that I'm a firm believer that proactive therapeutic drug monitoring has its best place during induction, to be honest.

I'm a big proponent that if you don't get the dose right in induction or at least at the first maintenance, for example, with infliximab -- we have data to support that -- that you will get higher antidrug antibody rates.

Maybe by proactively optimizing early, you could get away with reducing the need for combination therapy. We have seen that you do have 2 options, especially with infliximab, because that's where we have the most data.

I've come to understand that if you cannot proactively optimize with accurate drug concentrations, with, for example, the third and the fourth infusion and even maybe the fifth, to try and optimize it early, then a way to reduce antidrug antibodies, particularly with infliximab, would indeed be to use combination therapy.

I do actually agree that there's really 2 approaches to optimized infliximab, using proactive TDM early in induction, not just in maintenance, where most of the proactive data actually lies. We don't have a large amount of data about proactive induction, but there is data that is coming out to support that there are levels to achieve.

People asked, on the questions during the breakout, "What would be the ideal level, for example, at week 6 of infliximab?"

The data using some Bayesian modeling and using some pharmacokinetic dashboards suggests that a concentration of at least 17 at week 6 is associated with a week 14 level or concentration of at least 10. I'm a proponent that I like to use concentrations that are at least 7 at week 14.

We discussed the PANTS study, which was done in the UK, which definitively showed that in order to get better outcomes, even at week 14 but as well as at the end of a year, that patients who had infliximab drug concentrations of at least 7 at week 14 did better and adalimumab concentrations, interestingly, of at least 12 at week 14.

I think we're starting to see that we understand that if we have an aspiration to get a certain level at the first maintenance, that you could do that by understanding the concentration targets even as early as week 6.

There's even data to support that at week 2, believe it or not, at the second infusion, that drug concentration of at least 25 appears to be associated with you achieving a good week-6 drug concentration and then again at week 14.

There is some data that will emerge looking at what's the optimal induction regimen and how many people need accelerated dosing and whether or not that's superior to, for example, needing combination therapy. I'm excited to see how some of these studies actually pan out.

I think there was a nice theme today because I was able to look at using therapeutic drug monitoring in a more proactive outpatient setting and then thinking about it in an inpatient setting.

I hope that you enjoyed hearing a little bit more about therapeutic drug monitoring. I really hope you enjoy the rest of the meeting as well and look forward to hopefully seeing you in person in 2021. Thank you.